Transcriptional regulation of domesticated transposable elements-derived promoters in human genome

项目摘要 转座元件(TES)组成了人类基因组的大约一半，以及一些TE亚家族 甚至可以包含数十万个副本，例如直线和正弦元素。高度浓缩 TES序列中的转录因子结合位点使TES对宿主具有巨大的调节潜力 基因组。越来越多的证据表明，一些TES逃脱了表观遗传沉默，并积极参与了 宿主基因组的多个生物学过程。TES是脊椎动物Long起源的重要贡献者 非编码RNA，一些TES也被发现在早期发育和一些 终末分化组织。我们最近的研究发现，驯化的啮齿动物特有的TES可以发挥作用 作为启动子在小鼠组织中启动300多个基因的组织特异性转录 差异化。然而，驯化的TES衍生的启动子在人类基因组中如何调节 基因在不同组织和细胞类型中的转录，还没有明确的特征。例如，我们不知道 有多少基因可以由TES衍生的启动子在特定的人类组织中转录；我们不知道 关于来自同一组织的不同细胞类型中TES衍生的启动子的使用；最后，如何 人类基因组中驯化的TES创造了保守蛋白的新的组织特异性表达模式- 编码基因，仍然令人费解。因此，在这个拟议的项目中，我们将重点研究组织--和 由驯化的TES衍生启动子控制的细胞类型特异基因转录 人类基因组。利用大型财团产生的大数据，例如ENCODE、Roadmap 表观基因组学、GTEx和人类细胞图谱，我们将对驯化的 人类基因组中TES衍生的启动子。首先，我们将确定驯化的TES为 人类基因组中蛋白质编码基因和非编码基因的启动子，并进一步表征 利用我们已建立的转录本，驯化的TES衍生转录本的组织水平表达模式 组装管道对ENCODE和GTEx生成的组织批量RNA-seq数据进行分析。其次，我们 将研究驯化的TES来源的转录本的细胞类型特异性表达模式，通过 用新的生物信息学分析工具重建单细胞rna-seq数据分析。最后，我们会 应用比较基因组学方法创建同源TES衍生蛋白的表达矩阵- 跨多物种编码基因，构建系统发育树，探索表达模式 TES衍生蛋白编码基因在进化过程中的变化。

Project Summary Transposable elements (TEs) comprise roughly half of the human genomes, and some TE subfamilies can even contain hundreds of thousands of copies, such as LINE and SINE elements. Highly enriched transcriptional factor binding sites in the TEs sequence enable TEs the huge regulatory potential to the host genome. Mounting evidence suggests some of TEs escaped from epigenetic silencing and actively involved in multiple biological processes of host genome. TEs are significant contributors to the origin of vertebrate long non-coding RNAs, and some TEs are also found to play roles as promoters in early development and some terminally differentiated tissues. Our recent study found that domesticated rodent-specific TEs can play roles as promoters to initiate the tissue-specific transcription of more than 300 genes during mouse tissue differentiation. However, how the domesticated TEs-derived promoters in the human genome to regulate the gene transcription in distinct tissues and cell types, is not clearly characterized. For example, we do not know how many genes can be transcribed by TEs-derived promoters in particular human tissues; we have no idea about the usage of TEs-derived promoters in the different cell types from the same tissue; finally, how domesticated TEs in the human genome created novel tissue-specific expression pattern of conserved protein- coding genes, is still mystified. Thus, in this proposed project, we will focus on investigating the tissue- and cell type-specific gene transcription controlled by the domesticated TEs-derived promoters in the human genome. Leveraging the big data generated by large consortiums, e.g., ENCODE, Roadmap Epigenomics, GTEx, and Human Cell Atlas, we will perform a systematic survey of the usage of domesticated TEs-derived promoters in the human genome. Firstly, we will identify the TEs that were domesticated as promoters of protein-coding genes and non-coding genes in the human genome, and further characterize the tissue-level expression pattern of domesticated TEs-derived transcripts, by using our established transcripts assemble pipeline to analyze the tissue bulk RNA-seq data generated by ENCODE and GTEx. Secondly, we will investigate the cell-type-specific expression pattern of domesticated TEs-derived transcripts, by reconstructing the single-cell RNA-seq data analysis with novel bioinformatics analysis tool. Finally, we will apply comparative-genomics approaches to create the expression matrix of orthologous TEs-derived protein- coding genes across multi-species, and construct the phylogenetic trees to explore the expression pattern changes of TEs-derived protein-coding genes during evolution.